Prostate cancer updates were presented. Key points include:
1) The Gleason score is used to assess tumor aggressiveness and has shifted to include higher scores over time.
2) Screening results do not support widespread mass screening, but early detection may be offered to informed men with baseline PSA testing at age 40 and screening intervals of 8 years if initial PSA is low.
3) For localized disease, treatment options include active surveillance, radical prostatectomy, or radiation therapy depending on risk level and life expectancy. Deferred treatment may be appropriate for many cases.
3. Gleason score
The Gleason score is the sum of the two most common patterns
(grades 1-5) of tumour growth found. The Gleason score ranges
between 2 and 10, with 2 being the least aggressive and 10 the
most aggressive.
In needle biopsies, the worst grade should always be incorporated
in the Gleason score, even if comprising < 5% of the cancer.
During the past 20 years, there appears to have been a shift
towards higher Gleason scoring levels ,even in cases evaluating
microscopic foci of PCa. Some tumours previously given a Gleason
score of 6 (3 + 3) might be scored today as 7 (3 + 4) or higher.
4. SCREENING AND EARLY DETECTION
Based on the results of these two large, randomised trials, (PLCO)
(ERSPC) most if not all of the major urological societies conclude
that at present widespread mass screening for PCa is not
appropriate. Rather, early detection (opportunistic screening)
should be offered to the well-informed man
Two key questions remain open:
• At what age should early detection start?
• What is the screening interval for PSA and DRE?
5. A baseline PSA determination at age 40 years has been suggested,
upon which the subsequent screening interval may then be based
(GR: B).
A screening interval of 8 years might be enough in men with initial
PSA levels <1 ng/mL .
PSA testing in men older than 75 years is not recommended
because its early detection would not have any clinical impact .
6. DIAGNOSIS
The main diagnostic tools to obtain evidence of PCa include
DRE, serum concentration of PSA and transrectal ultrasonography
(TRUS). Its definite diagnosis depends on the histopathologic
verification of adenocarcinoma
Sextant biopsy is no longer considered adequate. At a glandular
volume of 30-40 mL, at least eight cores should be sampled. The
British Prostate Testing for Cancer and Treatment Study has
recommended 10 core biopsies (LE: 2a)
More than 12 cores are not significantly more conclusive (LE: 1a)
7. Endorectal MRI (e-MRI)
may allow for more accurate
local staging as Image quality
and localization improves
significantly with e-MRI , When
compared with DRE and TRUS.
8. e-MRI contributes significant incremental value for local PCa staging
,particularly in the pre-operative identification of extraprostatic
extension (EPE) and seminal vesicle invasion (SVI).
e-MRI could impact on the decision to preserve or resect the
neurovascular bundle (NVB) at the time of radical surgery
9. TREATMENT:
DEFERRED TREATMENT
There is a great difference between the incidence of PCa and
deaths from Pca
Several autopsy studies of people dying from different causes have
shown that while 60-70% of older men have histological PCa, a large
proportion of these tumours will not progress.
The incidence of small, localised, well-differentiated PCa is
increasing, mainly as a result of prostate-specific antigen (PSA)
screening and ‘multicore’ schemes of prostate biopsy
10. These data suggest that many men with localised PCa would not
actually benefit from definitive treatment.
With the aim of reducing the risk of overtreatment in this subgroup of
patients, two conservative management strategies of ‘watchful
waiting’ and ‘active surveillance’ have been proposed.
11. Watchful waiting (WW)
localised PCa (stage T1-T2, Nx-N0, M0)
the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)
randomised 695 patients with clinical stage T1-T2 to WW (348) or
radical prostatectomy (347) .
This study began after PSA screening was introduced into clinical
practice, but only 5% of men were diagnosed by screening.
12. After a median follow-up of 12.8 years, this study showed a
significant decrease in cancer-specific mortality, overall mortality,
metastatic risk progression and local progression in patients treated
with radical prostatectomy versus WW (LE: 1b).
Subgroup analysis showed that the overall difference was not
modified by PSA level (below or above 10 ng/mL) or by the Gleason
score (below 7 or above) at the time of diagnosis.
However, age at that the time of randomisation had a profound
impact, the benefit on overall survival and metastases free survival
being only seen for those below 65 years of age.
13. The Prostate Cancer Intervention Versus Observation Trial:
VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) is an
ongoing, controlled, multicentre, randomised clinical trial
comparing radical prostatectomy with WW in patients with clinical
stage T1-T2 disease.
731 patients with a median age of 67 years were enrolled.
approximately 43% of men had low-risk PCa, 36% had medium-risk
PCa, and 20% had high-risk PCa.
Follow-up is planned for 15 years, and the primary endpoint is the
overall mortality.
14. Preliminary unpublished results have been presented at the latest
AUA meeting .
The results suggested that overall there was a lack of survival
benefit.
However, there appeared to be an overall survival benefit in men
with an intermediate- and high-risk PCa, as well as a cancer specific
survival benefit in men with high-risk PCa or with a PSA above 10
ng/mL.
It appears that many small localised well-differentiated PCas will not
progress, and radical therapy may lead to substantial
overtreatment with resulting effects on the patients’ quality of life
and treatments costs.
15. Active surveillance
A variety of additional studies on active surveillance in clinically
organ confined disease have now been published.
16. All have confirmed that, in well-selected patients with very low-risk
disease, there was a very low rate of progression and cancer-
specific death, with only a few patients required delayed radical
intervention.
However, an extended follow-up is necessary to obtain definitive
results.
Thus, active surveillance might mean no treatment at all for patients
older than 70 years, while in younger patients, it might mean a
possible treatment delayed for years.
17. Indications
Stage T1a: well and moderately differentiated tumours. In younger
patients with a life expectancy of more than 10 years, re-evaluation
with PSA, TRUS and biopsies of the prostatic remnant is
recommended. (LE 2a)
Stage T1b-T2b: well and moderately differentiated tumours. In
asymptomatic patients with a life expectancy of < 10 years. (LE 2a)
In patients with the lowest risk of cancer progression: T1-2a, PSA <10
ng/mL, biopsy Gleason score <6 (at least 10 cores), <2 positive
biopsies, minimal biopsy core involvement (<50% cancer per
biopsy). (LE 2a)
18. Active surveillance selection is based on confirmatory biopsies.
Follow-up is based on DRE, PSA and repeated biopsies. The optimal
timing for follow-up is still unclear (yearly or every 2 years).
The trigger for patients being moved off active treatment is based
mainly on grade progression on repeated biopsies or at the
patient’s request.
19. ACTIVE MANAGMENT
Management decisions should be made after all treatments have
been discussed by a multidisciplinary team (including urologists,
radiation oncologists, medical oncologists and radiologists), and
after the balance of benefits and side effects of each therapy
modality has been considered by the patients with regard to their
own individual circumstances.
Patient must be informed about the likelihood of a multimodal
approach. In case of adverse tumour characteristics (positive
section margin, extraprostatic extension, or seminal vesicle invasion),
adjuvant radiotherapy may reasonably be used after recovery from
surgery.
When nodal involvement is detected after surgery, adjuvant ADT
may be selected.
20. When it comes to Pca treatment it is a matter of perspective
21. RADICAL PROSTATECTOMY
While it is the recommended choice In patients with low and
intermediate risk localised PCa (cT1a-T2b and Gleason score 2-7
and PSA <20 ng/mL) and life expectancy > 10 years. (LE1b)
It is optional in Patients with stage T1a disease and a life expectancy
>15 years or Gleason score 7. (LE 3)
Selected patients with low-volume, high-risk, localised PCa (cT3a or
Gleason score 8-10 or PSA > 20 ng/mL). (LE 3)
Highly selected patients with very-high-risk, localised PCa (cT3b-T4
N0 or any T N1) in the context of multimodality treatment.
22. neoadjuvant and adjuvant hormonal
treatment and radical prostatectomy
NHT before RP does not provide a significant OS advantage over
prostatectomy alone.
NHT before RP does not provide a significant advantage in DFS over
prostatectomy alone.
NHT before RP does substantially improve local pathological
variables such as organ-confined rates, pathological down-staging,
positive surgical margins, and rate of lymph node involvement.
Adjuvant HT following RP shows no survival advantage at 10 years.
Adjuvant HT following RP: the overall effect estimate for DFS is highly
significantly in favour of the HT arm.
23. DEFINITIVE RADIATION THERAPY
There are no randomised studies comparing radical prostatectomy
(RP) with either external beam radiation therapy (EBRT) or
brachytherapy for localised PCa.
However, the National Institutes of Health (NIH) consensus set up
in1988 remains available: external irradiation offers the same long-
term survival results as surgery.
moreover, EBRT provides a QoL at least as good as that provided by
surgery.
Intensity modulated radiotherapy (IMRT) +/- image guided (IGRT) is
the gold standard .
24. three-dimensional conformal radiotherapy (3D-CRT)
Anatomical data, acquired by scanning the patient in a treatment
position, are transferred to the 3D treatment planning system, which
visualises the clinical target volume and then adds a (surrounding)
safety margin. At the time of irradiation,
Intensity modulated radiotherapy(IMRT)
enables radiation oncologists to increase radiation doses, up to as
much as 86 Gy within the target volume, while respecting the
tolerance doses in organs at risk. Certainly, IMRT is the only safe
means of treatment delivery for dose escalation beyond 75 Gy
25. Immediate and delayed post-operative
external irradiation after radical prostatectomy
Three prospective randomised trials have assessed the role of
immediate post-operative radiotherapy
The EORTC study 22911
The study concludes that immediate post-operative radiotherapy
after surgery significantly improved 5-year clinical or biological
survival: 72.2% versus 51.8% (p < 0.0001)
Also the ARO trial 96-02 and the SWOG 8794 trial with similar
conclusion
26. Either immediate radiotherapy (ART) to the surgical bed upon
recovery of urinary function ; or clinical and biological monitoring
followed by salvage radiotherapy (SRT) before the PSA exceeds 0.5
ng/mL .
Early salvage radiotherapy provides the possibility of cure to
patients with an increasing or persisting PSA after RP.
More than 60% of patients who are treated before the PSA level rises
to more than 0.5 ng/mL will achieve an undetectable PSA level
again
27. Recommendations regarding
radiation therapy
In localized prostate cancer T1c-T2c N0 M0, 3D-CRT with or without
IMRT is recommended, even for young patients who refuse surgical
intervention. (LE 2)
For high-risk patients, long-term ADT prior to and during radiotherapy
is recommended because it results in increased overall survival.(LE 2)
In patients with pathological tumour stage T3 N0 M0, immediate
post-operative external irradiation after RP may improve overall
survival and biochemical and clinical disease-free survival with the
highest impact in cases of positive margins. (LE 1)
28. In patients with pathological tumour stage T2-3N0M0, salvage
irradiation is indicated in case of persisting PSA or biochemical
failure, but before the PSA level rises above 0.5 ng/mL. (LE 3)
In locally advanced prostate cancer T3-4 N0 M0, concomitant and
adjuvant hormonal therapy for a total duration of 3 years, with
external beam irradiation, is recommended because it improves
overall survival. (LE 1)
29. Experimental therapeutic options to
treat clinically localized PCa
All other minimally invasive treatment options - such as HIFU
microwave and electrosurgery - are still experimental or
investigational. For all of these procedures, a longer follow-up is
mandatory to assess their true role in the management of PCa.
30. Intermittent versus continuous ADT
Overall, eight randomized trials are underway the largest trial
available so far(still unpublished)has been presented at several
meetings.
A total of 1,386 patients relapsing after radiotherapy, given as either
primary treatment or for relapsing patients after surgery, were
randomized to continuous ADT or intermittent ADT.
Continuous treatment was for a fixed 8-month period.
Intermittent ADT was stopped when PSA < 4 ng/mL and resumed
when above 10 ng/mL. After a median 7 years of follow-up, the
median OS was 9.1 years in the continuous arm and 8.8 years in the
intermittent arm
31. This finding suggests that, even if continuous treatment provides a
specific survival difference compared to IAD, the survival difference
is completely counterbalanced by the increased specific toxicity of
continuous ADT
which therefore results in a lack of difference in OS survival, the
increasing of which remains the main objective
32. BIOCHEMICAL FAILURE AFTER
TREATMENT WITH CURATIVE INTENT
A recurrence of Ca P can be defined as:
•Following RP,PSA values > 0.2 ng/mL confirmed by two consecutive
measures.
•Following radiotherapy, a PSA value of 2 ng/mL above the nadir
after radiotherapy.
33. Diagnostic procedures for PSA
relapse following RP
bone scintigraphy and CT scans are of no additional diagnostic
value, unless the PSA serum levels are higher than 20 ng/mL or the
PSA velocity is more than 20 ng/mL/year.
Endorectal coil imaging is a useful technique to detect local
recurrences after RP .In a series of 48 patients, local recurrence was
correctly identified in 81%, with the mean PSA being 2 ng/mL at
diagnosis
Although eMRI appears to be very sensitive and predictive in
identifying local recurrences following RP, it is currently not a routine
imaging modality to be performed in every case, as local versus
systemic relapse must be differentiated at PSA levels < 0.5 ng/mL At
this PSA level, eMRI is not sufficiently sensitive or accurate.
34. Local recurrences are best treated by salvage radiation therapy
with 64-66 Gy at a PSA serum level < 0.5 ng/mL.
For patients with presumed local recurrence who are too unfit or
unwilling to undergo radiation therapy, expectant management
can be offered.
PSA recurrence indicative of systemic relapse is best treated by
early ADT resulting in decreased frequency of clinical metastases.
35. Castration resistant prostate cancer
Cancer of the prostate is a heterogeneous disease. Our knowledge
of the mechanisms involved in androgen independence, which is
now known as castration-resistant prostate cancer (CRPC), remains
incomplete but is starting to become clearer .
It is thought that androgen independence (now called castration
resistance) is mediated through two main, overlapping,
mechanisms, which are androgen-receptor (AR)-independent and
AR-dependent.
36. It is recommended to stop anti-androgen therapy once PSA
progression is documented.
No clear-cut recommendation can be made for the most effective
drug for secondary hormonal.
According to the positive results of this prospective randomised
clinical phase III trial (LE: 1), cabazitaxel should be considered in the
management of progressive CRPCA following docetaxel therapy.
Based on this second positive trial, in patients with relapse following
first-line docetaxel chemotherapy both Cabazitaxel and
Abiraterone are regarded as first-choice options for second-line
treatment